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\begin{document}

\title{Benefits of Early Combination Antiviral Treatment Containing Favipiravir
for COVID-19 in Thailand}



\author[1]{Kulkanya Chokephaibulkit}%
\author[2]{Narumol Sawanpanyalert}%
\author[1]{Rujipas Sirijatuphat}%
\author[3]{Piamlarp Sangsayunh}%
\author[4]{Poj Intalapaporn}%
\author[5]{Opass Putcharoen}%
\author[6]{Weerawat Manosuthi}%
\author[7]{Nattawan Palavutitotai}%
\author[8]{Worawan Samritmanoporn}%
\author[9]{Apatcha Pungjitprapai}%
\author[1]{Alan Maleesatharn}%
\affil[1]{Mahidol University Faculty of Medicine Siriraj Hospital}%
\affil[2]{Royal Thai Government Ministry of Public Health}%
\affil[3]{Central Chest Institute of Thailand}%
\affil[4]{Rajavithi Hospital}%
\affil[5]{Chulalongkorn University Faculty of Medicine}%
\affil[6]{Bamrasnaradura Infectious Disease Institute}%
\affil[7]{Lerdsin Hospital}%
\affil[8]{Nopparat Rajathanee Hospital}%
\affil[9]{Charoenkrung Pracharuk Hospital}%


\vspace{-1em}



  
  \date{May 24, 2024}


\begingroup
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\selectlanguage{english}
\begin{abstract}
We report the clinical outcomes following implementation of initial
COVID-19 treatment guidelines in Thailand. A composite poor outcome was
defined as death, ICU admission, requiring intubation, or high-flow
oxygen. 744 COVID-19 patients (48.8\% male) were included, median (IQR)
age was 37 (27-48) years {[}8.4\% \textgreater{}60 years{]} and 21.4\%
had pneumonia at admission. Admission \textless{}4 days from symptom
onset had a reduced risk of poor outcome. In a subgroup analysis,
favipiravir use reduced the risk of a poor outcome for patients admitted
\textless{}4 days from symptom onset (OR 0.320 (0.152-0.662), P=0.003).
Thai guidelines now include favipiravir to treat all symptomatic
COVID-19 patients.%
\end{abstract}%



\sloppy


\textbf{Benefits of Early Combination Antiviral Treatment Containing
Favipiravir for COVID-19 in Thailand}

\textbf{Running title:} Benefit of early favipiravir treatment in
Covid-19

\textbf{Authors:} Thailand COVID-19 Team

Kulkanya Chokephaibulkit\textsuperscript{1}

Narumol Sawanpanyalert\textsuperscript{2}

Rujipas Sirijatuphat\textsuperscript{1}

Piamlarp Sangsayunh\textsuperscript{3}

Opass Putcharoen\textsuperscript{4}

Weerawat Manosuthi\textsuperscript{5}

Poj Intalapaporn\textsuperscript{6}

Nattawan Palavutitotai\textsuperscript{7}

Worawan Samritmanoporn\textsuperscript{8}

Apatcha Pungjitprapai\textsuperscript{9}

Alan Maleesatharn\textsuperscript{1}

\textbf{Corresponding Author} : Kulkanya Chokephaibulkit, MD

Address: 2 Wanglang Road, Bangkoknoi

Bangkok 10700, Thailand

Tel: (66) 2-418-0545; Fax: (66) 2-418-0544

Email: kulkanya.cho@mahidol.ac.th

\textbf{Authors' Affiliation:}

1. Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok,
Thailand

2. Department of Medical Services, Ministry of Public Health,
Nonthaburi, Thailand

3. Central Chest Hospital, Nonthaburi, Thailand

4. Thai Red Cross Emerging Infectious Diseases Clinical Center, Faculty
of Medicine, Chulalongkorn University, Bangkok, Thailand

5. Bamrasnaradura Infectious Diseases Institute, Department of Diseases
Control, Ministry of Public Health, Nonthaburi, Thailand

6. Division of Infectious Disease, Medicine Rajavithi Hospital, Bangkok,
Thailand

7. Lerdsin Hospital, Bangkok, Thailand

8. Nopparat Rajathanee Hospital, Bangkok, Thailand

9. Department of Medicine, Charoenkrung Pracharak Hospital, Bangkok,
Thailand

\textbf{Conflict of interest:} All authors declare that they have no
conflicts of interest in relation to this work.

\textbf{Acknowledgement:}

Investigators of the Thailand COVID-19 Team: Kulkanya Chokephaibulkit,
Alan Maleesatharn, Faculty of Medicine Siriraj Hospital, Mahidol
University; Narumol Sawanpanyalert, Department of Medical Services,
Ministry of Public Health; Rujipas Sirijatuphat, Faculty of Medicine
Siriraj Hospital, Mahidol University; Piamlarp Sangsayunh, Central Chest
Hospital; Opass Putcharoen, Thai Red Cross Emerging Infectious Diseases
Clinical Center, Faculty of Medicine, Chulalongkorn university; Weerawat
Manosuthi, Bamrasnaradura Infectious Diseases Institute, Department of
Diseases Control, Ministry of Public Health; Poj Intalapaporn, Division
of infectious disease Medicine Rajavithi Hospital, Ministry of Public
Health; Nattawan Palavutitotai, Lerdsin Hospital; Worawan
Samritmanoporn, Nopparat Rajathanee Hospital; Apatcha Pungjitprapai,
Department of Medicine, Charoenkrung Pracharak Hospital.

The authors thank Tim R. Cressey, PhD (PHPT/IRD UMI 174, Faculty of
Associated Medical Sciences, Chiang Mai University, Chiang Mai,
Thailand) for his contribution to the manuscript.

\textbf{Abstract}

We report the clinical outcomes following implementation of initial
COVID-19 treatment guidelines in Thailand. A composite poor outcome was
defined as death, ICU admission, requiring intubation, or high-flow
oxygen. 744 COVID-19 patients (48.8\% male) were included, median (IQR)
age was 37 (27-48) years {[}8.4\% \textgreater{}60 years{]} and 21.4\%
had pneumonia at admission. Admission \emph{\textless{}} 4 days from
symptom onset had a reduced risk of poor outcome. In a subgroup
analysis, favipiravir use reduced the risk of a poor outcome for
patients admitted \emph{\textless{}} 4 days from symptom onset (OR 0.320
(0.152-0.662), P=0.003). Thai guidelines now include favipiravir to
treat all symptomatic COVID-19 patients.

\textbf{Keywords} : COVID-19, Favipiravir, Thailand

\textbf{Main text:} Thailand is one of the few countries that has been
able to successfully control the COVID-19 outbreak. As of January 10,
2021, there were 10,294 confirmed cases of COVID-19 in Thailand,
resulting in 69 deaths. Thailand encountered its first outbreak in early
March 2020 originating from attendees of a famous Thai Boxing
competition in Bangkok which rapidly spread to individuals in
surrounding bars and night clubs resulting in more than 2,500 cases. Due
to this rapid surge in cases, the Ministry of Public Health held
meetings with multidisciplinary experts, including infectious diseases
specialists, pulmonologists, intensivists, and policymakers, to develop
clinical practice guidelines to guide clinicians using the scientific
evidence available at that time. The first version of the COVID-19
guidelines was posted on March 21, 2020 and recommended (i) No antiviral
treatment for asymptomatic patients and (ii) Combination antiviral
treatment directed against different viral targets for symptomatic
cases, with the regimen dependent on the presence or absence of
pneumonia COVID-19 illness. For patients with non-pneumonia COVID-19
illness but with specific risk factors, e.g. age \textgreater{}60 years
or \textless{}5 years, BMI\textgreater{}35 kg/m\textsuperscript{2},
immunocompromised, diabetes, chronic conditions of lungs, kidney, liver,
cardiovascular or cerebrovascular diseases, or lymphocytes
\textless{}1,000 cells/mm\textsuperscript{3}, the recommended treatment
was chloroquine (CQ) (500 mg, twice daily) or hydroxychloroquine (HCQ)
(600 mg, twice daily on the first day, then 400 mg twice daily) plus a
boosted protease inhibitor (bPI) (lopinavir/ritonavir 400/100 mg, twice
daily or darunavir/ritonavir 600/100 mg, twice daily). A triple drug
combination of CQ or HCQ, a bPI, and favipiravir (FPV), an oral RNA
dependent RNA polymerase inhibitor (60 mg/kg/day twice daily on the
first day, then 20 mg/kg/day twice daily afterwards) was recommend for
patients with pneumonia COVID-19 illness. The use of FPV for only the
most severe cases was due to the limited availability at that time. The
duration of treatment was 5 days but could be extend to 10 days in cases
of severe pneumonia. Azithromycin was recommended as adjunctive
treatment for all symptomatic cases, particularly for severely ill
patients. All COVID-19 patients were hospitalized regardless of
symptoms. Our aim was to describe the clinical outcomes following
antiviral treatment according to these initial guidelines and identify
factors associated with a poor clinical outcome.

Nine large hospitals in Bangkok were invited to submit data on their
COVID-19 patients using standardized case record forms. Data collected
from March to June, 2020, included demographics, initial diagnosis,
antiviral and antibiotic treatment, clinical outcome, including the need
for oxygen therapy (intubated, high-flow, or lower oxygen support),
intensive care unit (ICU) admission, and death. A composite poor outcome
was defined as death, ICU admission, requiring intubation, or requiring
high-flow oxygen. If treatment was indicated, antiviral treatment was
initiated on the day of admission; however, favipiravir initiation may
be delayed for a day in some hospitals due to approval and drug delivery
process. Factors associated with the composite poor outcome were
assessed using multivariate analysis. The study was approved by the
local Ethics Committee.

A total of 744 COVID-19 patients (48.8\% male) were included in this
analysis with a median (interquartile range) age of 37 (27-48) years
{[}8.4\% \textgreater{}60 years{]}, 5.6\% were obese and 16.5\% had
underlying conditions. At hospital admission, 28.4\% were asymptomatic,
50.2\% had non-pneumonia illnesses, of which 22.7\% had risk factors,
and 21.4\% had pneumonia (Figure 1). 637 (85.6\%) cases received
antiviral treatment in compliance with the guidelines. Overall, there
were 8 (1.1\%) deaths, 66 (8.9\%) required ICU admission, 17 (2.3\%)
required intubation, and 19 (2.6\%) required high-flow oxygen. Seventy
(9.4\%) of patients had at least one of these outcomes (composite poor
outcomes).

In univariate analysis among symptomatic patients, factors associated
with a higher risk of a composite poor outcome were: being male (odd
ration {[}OR{]} 1.89 (95\% confidential interval {[}CI{]} 1.12-3.20),
P=0.018), \textgreater{}60 years-old (OR 4.42 (2.36-8.27),
P\textless{}0.001), obesity (OR 2.79 (1.32-5.88), P=0.007) , underlying
risk condition (OR 4.14 (2.45-6.99), P\textless{}0.001), pneumonia at
admission (OR 11.51 (6.32-20.94), P\textless{}0.001), receiving an
initial regimen containing FPV (OR 10.65 (5.62-20.17),
P\textless{}0.001) and azithromycin use (OR 4.52 (2.68-7.62),
P\textless{}0.001). Admission to the hospital within 4 days from symptom
onset significantly reduced the risk of a composite poor outcome (OR
0.30 (0.17-0.52), P\textless{}0.001), and this remained significant
among patients with pneumonia at presentation (OR 0.34 (0.16-0.72),
P=0.005), but not among patients with non-pneumonia illness (OR 0.65
(0.24-1.77), P=0.397). The longer time to hospital admission
significantly increased the risk of poor outcome (OR 1.10 (1.04-1.16),
P=0.001), i.e. the risk of a composite poor outcome increased 10\% each
day from symptom onset until hospital admission.

In a multivariate analysis of symptomatic patients, factors associated
with a composite poor outcome were an underlying risk conditions,
receiving an initial regimen containing FPV, and azithromycin use; while
admission within 4 days of onset of symptoms was associated with a
reduced risk of a poor composite outcome (Table 1).

A triple drug antiviral regimen of CQ/HCQ + bPI + FPV was associated
with a composite poor outcome but this was likely due to its use only in
the sickest patients. However, in a subgroup analysis, regimens with FPV
reduced the risk of a poor outcome for patients
admitted\emph{\textless{}} 4 days from symptom onset, compare to after 4
days, even after adjusting for confounding factors (OR 0.320
(0.152-0.662), P=0.003) (Table 2). This benefit was not observed for
patients receiving regimens using CQ/HCQ plus bPI without FPV.

Large studies have reported no benefit of
lopinavir\textsuperscript{1,2}and
hydroxychloroquine\textsuperscript{3-5}and we also observed no clear
benefit of this dual treatment combination. Recent data from the
open-label randomized SOLIDARITY study,\textsuperscript{6} led by WHO,
found that neither remdesivir, hydroxychloroquine, lopinavir, nor
interferon beta-1a treatment reduce overall mortality. No benefit of
remdesivir in terms of all-cause mortality was also reported in the
ACTT-1 trial,\textsuperscript{7} but remdesivir did significantly
decrease the time to recovery (10 vs 15 days, RR 1\selectlanguage{ngerman}·29, 95\% CI
1·12--1·49), with a clear benefit for patients starting treatment within
10 days of symptom onset. The approval of remdesivir for COVID-19
treatment is encouraging but widespread access is expected to be limited
in most resource-limited settings, including Thailand. Favipiravir has a
similar antiviral mechanism to remdesivir and can easily be scaled up in
Asia due to its lower cost and simpler oral administration. Studies have
shown favipiravir to be effective in viral clearance and improve
clinical outcomes when compared to
lopinavir/ritonavir\textsuperscript{8} or with
arbidol\textsuperscript{9}, or without antiviral
treatment.\textsuperscript{10} Initiation of FPV `early' compared to
`late' (6 days later) was found to reduce the time to defervescence in
Japanese adults admitted with COVID-19 who were asymptomatic or mildly
ill. Data from our study, while observational, indicates that early
treatment (\textless{}4 days from symptom onset) with a combination of
antivirals containing favipiravir reduces the risk of a poor outcome.
These data build on the evidence that early antiviral treatment could be
beneficial while later antiviral treatment after the process of
hyperinflammatory has kicked in, and viral
load\textsuperscript{11}waning, is less effective, and instead a
glucocorticoid would help reduced mortality.\textsuperscript{12}

The initial Thai guidelines were based on available data at that time
with many of the evidence based on \emph{in-vitro} data. Considering the
recent literature, along with these local data, Thai guidelines were
recently revised to stop using CQ/HCQ plus bPI, and recommend using
favipiravir early in the course of illness for symptomatic patients
independent of risk factors. It is conceivable that early treatment with
FPV per initial guidelines could have contributed towards the relatively
low mortality observed in our setting. In the second wave in Thailand,
favipiravir plays an important role for the treatment of COVID-19.

\textbf{References}

\begin{enumerate}
\tightlist
\item
  Cao B, Wang Y, Wen D, et al. A trial of lopinavir--ritonavir in adults
  hospitalized with severe COVID-19. N Engl J Med 2020; 382:1787-1799.
\item
  RECOVERY Collaborative Group. Lopinavir-ritonavir in patients admitted
  to hospital with COVID-19 (RECOVERY): a randomised, controlled,
  open-label, platform trial. Lancet 2020;396:1345-1352.
\item
  The RECOVERY Collaborative Group. Effect of hydroxychloroquine in
  hospitalized patients with COVID-19. N Engl J Med 2020;383:2030-2040
\item
  Rosenberg ES, Dufort EM, Udo T, et al. Association of treatment with
  hydroxychloroquine or azithromycin with in-hospital mortality in
  patients with COVID-19 in New York state. JAMA 2020;323:2493-2502.
\item
  Cavalcanti AB, Zampieri FG, Rosa RG, et al. Hydroxychloroquine with or
  without azithromycin in mild-to-moderate COVID-19. N Engl J Med
  2020;383:2041-2052.
\item
  WHO Solidarity trial consortium. Repurposed antiviral drugs for
  COVID-19 --interim WHO Solidarity trial results. N Engl J Med 2020
  December 2. {[}Epub ahead of print{]}
\item
  Beigel JH, Tomashek KM, Dodd LE. et al. Remdesivir for the treatment
  of COVID-19---final report. N Engl J Med 2020; 383: 1813-1826.
\item
  Cai Q, Yanga M, Liu D, et al. Experimental treatment with favipiravir
  for COVID-19: An open-label control study. Engineering
  2020;6:1192-1198.
\item
  Chen C, Zhang Y, Huang J, et al. Favipiravir versus arbidol for
  COVID-19: A randomized clinical trial. BMJ 2020 April 15. {[}Epub
  ahead of print{]}
\item
  Ivashchenko AA, Dmitriev KA, Vostokova NV, et al. Avifavir for
  treatment of patients with moderate COVID-19: Interim results of a
  phase II/III multicenter randomized clinical trial. Clin Infect Dis
  2020 August 9. {[}Epub ahead of print{]}
\item
  Weiss A, Jellingsø M, Sommera MOA. Spatial and temporal dynamics of
  SARS-CoV-2 in COVID-19 patients: A systematic review and
  meta-analysis. EBioMedicine 2020; 58:102916.
\item
  RECOVERY Collaborative Group. Dexamethasone in hospitalized patients
  with COVID-19 - preliminary report. N Engl J Med 2020 July 17;
  58:102916.
\end{enumerate}

\textbf{Table 1} . Univariate and multivariate analysis among
symptomatic COVID-19 patients and risk factors associated with composite
poor outcome (defined as at least one of the outcomes: requiring
high-flow oxygen therapy, being intubated with mechanical ventilation,
admission to ICU, or death).\selectlanguage{english}
\begin{longtable}[]{@{}llllllll@{}}
\toprule
\begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Total} \textbf{(n=533)}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Composite} \textbf{Poor Outcome}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Composite} \textbf{Poor Outcome}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{OR}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{P-value}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{Adjusted OR}\strut
\end{minipage} & \begin{minipage}[b]{0.12\columnwidth}\raggedright\strut
\textbf{P-value}\strut
\end{minipage}\tabularnewline
\midrule
\endhead
\begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{Yes} (n=70)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\textbf{No} (n=463)\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.12\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Gender; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Gender; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Gender; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Gender; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Male\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
279 (52.3)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
46 (65.7)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
233 (50.3)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.89 (1.12-3.20)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.018\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.58 (0.82-3.06)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.170\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Female\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
254 (47.7)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
24 (34.3)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
230 (49.7)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Age; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age \textless{}60 years\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
478 (89.7)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
51 (72.9)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
427 (92.2)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Age [?]60 years\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
55 (10.3)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
19 (27.1)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
36 (7.8)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4.42 (2.36-8.27)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.93 (0.86-4.33)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.111\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Underlying risk condition; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Underlying risk condition; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Underlying risk condition; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Underlying risk condition; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
120 (22.5)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
34 (48.6)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
86 (18.6)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4.14 (2.45-6.99)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.95 (1.01-3.73)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.045\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
413 (77.5)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
36 (51.4)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
277 (81.4)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Obesity; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
40 (7.5)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
11 (15.7)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
29 (6.3)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.79 (1.32-5.88)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.007\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
493 (92.5)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
59 (84.3)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
434 (93.7)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
-\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Presented with pneumonia; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Presented with pneumonia; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Presented with pneumonia; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Presented with pneumonia; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
159 (29.8)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
54 (77.1)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
105 (22.7)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
11.51 (6.32-20.94)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1.90 (0.88-4.11)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.103\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
374 (70.2)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
16 (22.9)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
358 (77.3)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Time from onset of symptoms to hospital admission; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Time from onset of symptoms to hospital admission; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Time from onset of symptoms to hospital admission; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Time from onset of symptoms to hospital admission; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Within 4 days\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
284/531 (53.5)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
20/70 (28.6)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
264/461 (57.3)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.30 (0.17-0.52)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.44 (0.23-0.84)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.014\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textgreater{}4 days\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
247/531 (46.5)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
50/70 (71.4)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
197/461 (42.7)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Initial antiviral regimen; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Initial antiviral regimen; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Initial antiviral regimen; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Initial antiviral regimen; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
With FPV\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
138/384 (35.9)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
54 (79.4)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
84 (26.6)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
10.65 (5.62-20.17)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
5.31 (2.44-11.56)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Non-FPV\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
246/384 (64.1)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
14 (20.6)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
232 (73.4)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Received Azithromycin; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Received Azithromycin; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Received Azithromycin; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textbf{Received Azithromycin; n (\%)}\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
Yes\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
129 (24.2)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
37 (52.9)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
92 (19.9)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
4.52 (2.68-7.62)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\textless{}0.001\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
2.22 (1.17-4.21)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
0.014\strut
\end{minipage}\tabularnewline
\begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
No\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
404 (75.8)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
33 (47.1)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
371 (80.1)\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
1\strut
\end{minipage} & \begin{minipage}[t]{0.10\columnwidth}\raggedright\strut
\strut
\end{minipage}\tabularnewline
\bottomrule
\end{longtable}

\textbf{Table 2} . Multivariable analysis of confounding effect to
combination antiviral treatment with favipiravir in COVID-19 patients
hospitalized within 4 days of symptom onset and composite poor outcome
(defined as at least one of the poor outcomes: requiring high-flow
oxygen therapy, being intubated with mechanical ventilation, admission
to ICU, or death).\selectlanguage{english}
\begin{longtable}[]{@{}lllll@{}}
\toprule
\textbf{Variable} & \textbf{N\textsuperscript{a}} & \textbf{OR (95\%CI)}
& \textbf{\% Change in OR from base model} &
\textbf{P-value}\tabularnewline
\midrule
\endhead
Unadjusted base model: Receiving Favipiravir with any other drugs and
time to admission within 4 days\textsuperscript{b} & 140 & 0.320
(0.152-0.662) & Ref & 0.003\tabularnewline
Adjusted for: & & & &\tabularnewline
Age (years) & 140 & 0.341 (0.161-0.723) & 6.6\% & 0.005\tabularnewline
Age \textgreater{} 60 years & 140 & 0.328 (0.156-0.691) & 2.5\% &
0.003\tabularnewline
Gender & 140 & 0.330 (0.156-0.696) & 3.1\% & 0.004\tabularnewline
Having risk condition & 140 & 0.316 (0.150-0.666) & 1.3\% &
0.002\tabularnewline
Obesity & 140 & 0.331 (0.156-0.700) & 3.4\% & 0.004\tabularnewline
Having at least one risk factors & 140 & 0.325 (0.153-0.689) & 1.6\% &
0.003\tabularnewline
Received Azithromycin & 140 & 0.340 (0.159-0.726) & 6.3\% &
0.005\tabularnewline
Compliance to Thai guideline & 140 & 0.302 (0.142-0.643) & 5.6\% &
0.002\tabularnewline
\bottomrule
\end{longtable}

a. 140 patients who received favipiravir only or with any other drugs b.
Among patients who received favipiravir with any other drugs, comparison
between time to admission within 4 days and \textgreater{}4
days\textbf{Figure 1. Summary of patients clinical presentation, risk
factors*, and initial antiviral treatment.}*Risk factors include age
\textgreater{}60 years or \textless{} 5 years, obesity defined as
BMI\textgreater{}35 kg/M2, or other conditions that may be associated
with severe COVID-19 illness such as immunocompromised conditions,
diabetes, chronic conditions of lungs, kidney, liver, cardiovascular or
cerebrovascular diseases, total lymphocyte counts \textless{}1,000
cells/mm3. Abbreviation: CQ: chloroquine, HCQ: hydroxychloroquine, bPI:
boosted protease inhibitor (ritonavir boosted lopinavir or darunavir),
FPV: favipiravir

\selectlanguage{english}
\FloatBarrier
\end{document}

